16beta-methyldesoxycorticosterone 21-acetate



United States Patent Office 3,210,393 Patented Oct. 5, 1965 Theinvention relates to a new pharmacologically active compound and to aprocess for manufacturing the same.

The new compound of the invention is 16fi-methyldesoxycorticosterone21-acetate of the formula:

CHZOCOCH3 This new compound possesses hypertensive activity butsurprisingly, unlike desoxycorticosterone, has substantially no effecton electrolyte metabolism.

The process of the invention for producing the abovementioned compoundcomprises treating pregna-5,l6-diene-3fl,21-diol-20-one ZI-acetate withdiazomethane, heating the 16a,17a-diazomethylene derivative obtained at140-170 C., hydrogenating the resulting16i3-methylpregna-5,16-diene-3/3,21-diol-20-one 21-acetate to 16(3-methyl-pregna--ene-3fi,21-diol-20-one .21-acetate and converting thelast mentioned compound to 16/3-methyldesoxycorticosterone acetate.

The reaction scheme is as follows:

CI-I OCOCHa AT? (:A/\/ \J W) GHzOCOCI-Is /\l N C 5 110- oi. as;

CHgO C OGHs CH O C 0 CH3 The production of the new steroid isillustrated by the following example:

EXAMPLE 1 160a,] 7u-diaz0methylene-pregn-S w ne-313,2 1 -dz'0l- 20-0neZI-acetate (compound II) To a solution of 25 g. ofpregna-S,16-diene-3,8,21-dio1- 20-one 21-acetate in 300 ml. oftetrahydrofuran, chilled to 10 C., a dry ether solution of diazomethane,prepared from g. of nitrosomethylurea, is slowly added. After one hourthe temperature is allowed to rise to +5 C. and the solution storedovernight at 5 C. Evaporation to dryness gives 27.7 g. of thecrystalline compound II, M.P. 165l69 C. which is sufficiently pure forthe next step. A small amount is purified by crystallization fromacetone giving an analytically pure sample; M.P. 179-180 C.; 24.3(c.:0.946, CHCl LR. (Nujol mull): 3465 (OH), 1753 (C=O), 1556 (N N) cmfAnalysis.-Calculated for C H O N C, 69.55; H, 8.27; N, 6.76. Found: C,69.70; H, 8.48; N, 6.86.

16-methyl-pregna-5J6-diene-3,B,21-di0l-20-0ne 21 acetate (compound III)A suspension of 25.7 g. of compound II (MP. 165- 169) in ml. of paraffinoil is slowly heated with elfective stirring to C. At this temperaturenitrogen evolution takes place and continues spontaneously without anyadditional heating; the temperature reaches C. As soon as the evolutionof gas stops, the solution is cooled while stirring down to 90 C. andtreated with ml. of hexane. The product which separates on cooling iscollected, washed once more with hexane and dried: 28.7 g.; M.P. l60172C. The raw material is recrystallized up to a constant melting point.Yield 14.5 g. (63% of theory); M.P. 187-190 C.; [(11 85 (c.:0.954, CHClA 252 m (C H OH); 6 (mol.) 8400; LR. (Nujol mull): 3465 (OH), 1753(O.COCH 1660 (20 C=O), 1596 (Ci) cm.-

Analysis.-Ca1culated for C I-1 0 C, 78.82; H, 8.88. Found: C, 74.66; H,8.96.

1 6 ,B-mcthyl-pregn-S -ene-3 6,21 -di0l-20-one 21 acetate (compound IV)A solution of 10.8 g. of compound III in 2200* ml. of methanol istreated with 20 g. of Raney-nickel and shaken with H at room temperatureand normal pressure till any gas adsorption stops. The catalyst isfiltered off and the solution evaporated to dryness. The crude oil isdissolved in acetone and evaporated to dryness in vacuo. The While solidproduct is dissolved in 100 ml. of ether and the solution filtered andevaporated till cloudiness appears. After storage at 5 C., 7.2 g. ofcompound IV are collected: M.P. 135-142 C. A small sample isrecrystallized several times till analytically pure. M.P. ISO-152 C.;[a] +0.2 (c.=0.5, CHCl LR. (Nujol mull): 3540 broad (OH), 1747 (OCOCH3),1720 (C O) cmf Analysis.Calculated for C I-1 C, 74.21; H, 9.34. Found:C, 73.95; H, 9.78.

J 6 ,B-methyl-pregn-4-ene-2] -0'l-3,20-di0ne 21 -aceta'te (compound V) Asolution of 5.2 g. of compound IV in 145 ml. of toluene and 43 ml. ofcyclohexanone is distilled to remove 15 ml. of toluene and a solution of2 g. aluminium isopropoxide in 16 ml. of toluene is added thereto. Themixture is refluxed for 3 hours, then cooled and Washed with a saturatedsolution of Seignette salt, then with diluted NaOH solution andeventually with water. The organic phase is dried over Na SO evaporatedto dryness and extracted several times with hot petroleum ether. Afterdrying in vacuo the oily residue is slurried with ether; 1 g. ofcompound V, M.P. 133-140 C. can be With petroleum ether. An additionalcrop of compound V, 1054 mg, M.P. 130138 C., is obtained. Both crops2.05g.are crystallized from methanol. Yield: 1.9 g.; M.P. 142144 C.; [a]+148 (c.=0.925, di- OXane); A 241 III/L (CH OH).

Analysis.Calculated for C H O C, 74.58; H, 8.81.

Found: C, 74.57; H, 8.71.

We claim: 16/3-methyldesoxycorticosterone 21-acetate.

References Cited by the Examiner UNITED STATES PATENTS 3,009,936 11/61Hershberg et al 260397.47 3,054,725 9/62 Ilavsky et al. 260-397473,067,217 12/62 Muller et al 260397.47

OTHER REFERENCES Taub et a1.: J. Amer. Chem. Soc., vol. 80, No. 16, Aug.20, 1958, p. 4435.

LEWIS GOTTS, Primary Examiner.

